BACKGROUND Although correlation between cytosine-adenine-guanine (CAG) repeat length and age of Huntington disease (HD) onset is well known, improved prediction of onset would be advantageous for clinical trial design and prognostic counseling. We compared genetic, demographic, motor, cognitive, psychiatric, functional and imaging measures for tracking progression and predicting conversion to manifest HD. METHODS N=1078 research participants with the gene mutation for HD, but without a rating of 4 on the Diagnostic Confidence Level (DCL) following administration of the 15-item motor assessment of the Unified Huntington’s Disease Rating Scale. Participants were from 33 world wide sites and followed for up to 12 years (mean=5, SD=3·3) over the period 2001–2013. A subset of 225 participants prospectively converted to manifest HD according to the DCL (“meets the operational definition of the unequivocal presence of an otherwise unexplained extrapyramidal movement disorder in a subject at risk for HD” with ≥99% confidence). Joint modeling of longitudinal and survival data was used to examine the extent to which baseline and change of 40 variables analyzed separately was predictive of CAG-adjusted age at motor diagnosis. FINDINGS Cross-sectional and longitudinal clinical and imaging measures were significant predictors of motor diagnosis beyond CAG repeat length and age. The strongest predictors in the top three phenotypic domains were total motor score (motor), putamen volume (imaging), and Stroop word test (cognitive). A one standard deviation (SD) difference in total motor score increased the risk of a motor diagnosis by 3·1 times (95% CI=[2·3,4·2]), one SD loss in putamen volume increased risk by 3·3 times ([2·4,4·7]) and one SD cognitive decline increased risk by 2·3 ([1·9,2·9]). INTERPRETATION Prediction of HD diagnosis can be considerably improved beyond that obtained by CAG repeat length and age alone. Such knowledge about potential predictors of manifest HD should inform discussions about revisions to guidelines for diagnosis, and prognosis, and counselling, and might be useful in guiding selection of participants and outcome measures for clinical trials. FUNDING National Institutes of Health, National Institute of Neurological Disorders and Stroke, and CHDI Foundation, Inc.

Practice effects, defined as improvements in cognitive test performance due to repeated exposure to the test materials, have traditionally been viewed as sources of error. However, they might provide useful information for predicting cognitive outcome. The current study used three separate patient samples (older adults with mild cognitive impairments, individuals who were HIV+, individuals with Huntington's disease) to examine the relationship between practice effects and cognitive functioning at a later point. Across all three samples, practice effects accounted for as much as 31-83% of the variance in the follow-up cognitive scores, after controlling for baseline cognitive functioning. If these findings can be replicated in other patients with neurodegenerative disorders, clinicians and researchers may be able to develop predictive models to identify the individuals who are most likely to demonstrate continued cognitive decline across time. The ability to utilize practice effects data would add a simple, convenient, and non-invasive marker for monitoring an individual patient's cognitive status. Additionally, this prognostic index could be used to offer interventions to patients who are in the earliest stages of progressive neurodegenerative disorders.

These findings underscore the importance of personality on outcomes in MS and point to the need for more clinical attention and research in this area.

Distinguishing practice effects from other factors in repeated neuropsychological assessments are discussed in the context of research studies and clinical/forensic assessments. Potential methodological procedures for reducing the impact of practice effects in research settings are outlined. In contrast, the potential clinical utility and interpretation of practice effects in clinical assessments and forensic evaluations are highlighted.

Background/Aims: Patients with mild cognitive impairment (MCI) experience cognitive declines and often report significant emotional/behavioral changes. Despite this, few studies have examined the impact of MCI on caregiver burden. The purpose of this study was to confirm the presence of caregiver burden in MCI and examine the relationship between burden and patients’ neuropsychological, behavioral and emotional functioning. Methods: The current study included 51 individuals who had been diagnosed as having MCI using Petersen’s criteria. The patients underwent a thorough neuropsychological evaluation and completed the Beck Depression Inventory and Cognitive Difficulties Scale. The caregivers completed the Zarit Burden Interview and the Revised Memory and Behavior Checklist. Results: More than 30% of the caregivers reported clinically significant burden. Increased caregiver burden was associated with a longer course of cognitive symptoms, patient reports of worse depression and greater cognitive difficulties, and informant reports of patients having more behavior, mood and memory problems. Caregiver burden was not significantly associated with patients’ neuropsychological test performance. Conclusion: The results highlight the importance of addressing patients’ behavioral and emotional difficulties, as well as caregiver burden, as part of the clinical exam in MCI.

This study provides Class I evidence which does not support the hypothesis that 10 mg of donepezil daily for 24 weeks is superior to placebo in improving cognition as measured by the SRT in people with MS whose baseline RAVLT score was 0.5 SD or more below average.

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Background Huntington disease (HD) is associated with decline in cognition and progressive morphological changes in brain structures. Cognitive reserve may represent a mechanism by which disease-related decline may be delayed or slowed. The current study examined the relationship between cognitive reserve and longitudinal change in cognitive functioning and brain volumes among prodromal (gene expansion-positive) HD individuals. Methods Participants were genetically-confirmed individuals with prodromal HD enrolled in the PREDICT-HD study. Cognitive reserve was computed as the composite of performance on a lexical task estimating premorbid intellectual level, occupational status, and years of education. Linear mixed effects regression (LMER) was used to examine longitudinal changes on 4 cognitive measures and 3 brain volumes over approximately 6 years. Results Higher cognitive reserve was significantly associated with a slower rate of change on one cognitive measure (Trail Making Test, Part B) and slower rate of volume loss in two brain structures (caudate, putamen) for those estimated to be closest to motor disease onset. This relationship was not observed among those estimated to be further from motor disease onset. Conclusions Our findings demonstrate a relationship between cognitive reserve and both a measure of executive functioning and integrity of certain brain structures in prodromal HD individuals.